Cancer affects millions of people each year. While considerable progress in the treatment of cancer has been made over the last decades, better treatment is still in great need.
In the art there is a great number of chemical and biological agents of demonstrated or suggested use in the treatment of cancer, among them exosomes of human origin.
Exosomes are nano-sized vesicles which can carry antigen as well as co-stimulatory molecules. Dendritic cells (DC) are antigen-processing and antigen-presenting cells pertaining to the mammalian immune system. In a state activated by antigen they interact with B cells and T cells to trigger their adaptive immune response. During the last decade dendritic cell (DC) derived exosomes have been tested in animal models and clinical trials for the treatment of malignant disease. DC derived exosomes can stimulate T cell activation in vitro and in vivo, and eradicate tumors in mice (Amigorena S, Anti-tumour immunotherapy using dendritic-cell-derived exosomes. Res Immunol 1998, 149(7-8): 661-662; Zitvogel L et al., Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998, 4(5): 594-600). Different cell types produce exosomes with phenotypes that reflect their cells of origin (Johansson S M et al., Different types of in vitro generated human monocyte-derived dendritic cells release exosomes with distinct phenotypes. Immunology 2008, 123: 491-499. Segura, et al., Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. Blood Cells Mol Dis 2005, 35: 89-93). The current dogma says that dendritic cell derived exosomes are preferred to B cell derived ones, since the corresponding cell, dendritic cell, is more efficient in stimulating naïve T cells compared to B cells. However, B cell exosomes have never been explored in this context.
A role for B cells in producing a complete T cell response has been suggested (Ron Y and Sprent J, T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes. J Immunol 1987, 138(9): 2848-2856). Lately, Ding et al. showed that targeting of antigens to B cells can potentiate specific T cell responses and break immune tolerance (Ding C et al., Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1. Blood 2008, 112(7): 2817-2825). Furthermore, new data show that B cells are particularly important in achieving long term T cell immunity (Whitmire J K et al., Requirement of B Cells for Generating CD4+ T Cell Memory. J Immunol 2009, 182(4): 1868-1876). Exosomes can carry B cell epitopes; B cell response is needed for T cell proliferation (Quazi K R et al., Antigen loaded exosomes alone induce Th1 type memory through a B-cell dependent mechanism. Blood 2009, 113:2673-2683). It is debated whether exosomes are able to stimulate T cells by themselves (Admyre C et al., Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur J Immunol 2006, 36: 1772-1781) or if other cells are needed as intermediates (Vincent-Schneider H et al. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol 2002, 14: 713-722) and antigen specificity may influence the direct interaction between exosomes and T cells. Exosomes of different origin target specific cell populations in human blood (Johansson S M et al., in: Johansson S M, Exosomes—nano-vesicles in immune regulation. Thesis for doctoral degree 2008, Karolinska Institutet, Stockholm, ISBN 978-91-7409-058-1.
Complement component (3d/Epstein Barr virus) receptor 2 (CD21; also: CR2) is a receptor on the surface of B cells involved in their activation and maturation.
Epstein-Barr virus (EBV) is a human lymphotropic herpes virus. EBV can immortalize primary B cells into lymphoblastoid cells that can be grown in vitro. EBV glycoprotein gp350 binding to CD21 is critical for viral attachment to B cells (Young K A et al., Molecular basis of the interaction between complement receptor type 2 (CR2/CD21) and Epstein-Barr virus glycoprotein gp 350. J Virol 2008, 82: 11217-11227). Exosomes from EBV-transformed B cells have been reported to carry the EBV-encoded latent membrane protein 1 (LMP1) which has a T-cell inhibitory activity (Keryer-Bibens C et al., Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer 2006, 6: 283).